Project Summary The continuing prevalence of SARS-CoV-2 coronavirus cases has led to an urgent need to develop strategies for identifying patients who are likely to have mild vs. severe disease to optimally allocate health care resources. It is also critical that we understand why certain patients develop severe disease. One possible mechanism is through antibody-dependent enhancement (ADE) a phenomenon well documented for other viruses including SARS. In order to develop safe and effective vaccines, it is essential that we determine whether the humoral immune response to Covid-19 induces antibodies that can mediate ADE and to understand which aspects of the immune response to the virus correlate with good clinical outcomes. Addressing this knowledge gap quickly is necessary to inform vaccine trials, which are already underway or are about to start. Our multidisciplinary team has the expertise to address the issues described above. As an independent non-profit research institution, we are nimble and responsive to evolving health needs. Besides studying a spectrum of patients from across Oklahoma, we are uniquely positioned to look at the consequences of SARS- CoV-2 infection for Native Americans. Native Americans have the shortest life expectancy of any ethnic group in the US with higher rates of nearly every co-morbidity associated with higher mortality with SARS-CoV-2 infection (obesity, diabetes, heart disease, and hypertension). Oklahoma is home to 39 federally recognized tribes and has the 2nd highest number of American Indians (482,760 according to the 2010 census, and highest percentage, >10%) in the US. Through our Oklahoma Shared Clinical and Translational Resources (OSCTR), we have partnerships with 5 major tribes, urban Indian clinics and the Southern Plains Tribal Health Board representing all tribes in Oklahoma, Texas and Kansas. Through these and other interactions, we have strong ties to obtain samples from Native Americans with SARS-CoV-2 infection and exposure. Specific Aims 1. Identify biomarkers and mechanisms of severe Covid-19 disease pathogenesis 2. Characterize the humoral immune response to SARS-CoV-2 infection 3. Characterize the T cell immune response to SARS-CoV-2 infection Whenever feasible, we will compare the responses of Native Americans to those of European Americans to determine whether Native Americans experience worse outcomes to SARS-CoV-2 infection and if so, which parts of the immune response is/are suboptimal. We will also compare the responses of individuals with mild vs. severe disease. The knowledge gained should lead to better care for individuals with Covid-19 disease.